Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer

Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.-Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.Scopu

Evaluation of Cardiotoxicity in HER-2 Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab

PURPOSE/OBJECTIVE(S): Trastuzumab is associated with cardiac dysfunction in HER-2 positive breast cancer patients. The current study examines the effect of radiation therapy on cardiotoxicity in this patient population. MATERIALS/METHODS: The HERA trial is a phase III prospective randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive breast cancer. The current study is a retrospective analysis of 3,321 trial patients treated with trastuzumab with or without radiotherapy. Cardiac function was closely monitored over a median follow up period of 10 years. The primary endpoint of the study was to determine the effect of radiation therapy on left ventricular ejection fraction (LVEF) and the occurrence of cardiovascular events. RESULTS: Patients were divided to three groups: 1270 subjects received trastuzumab and left-sided radiation therapy (group 1), 1271 subjects received trastuzumab and right-sided radiation therapy (group 2) and 780 had trastuzumab with no radiation therapy (group 3). The incidence of significant LVEF decline was 28.22%, 29.54% and 26.85%, respectively with no significant differences among the three groups (P-value = 0.484). The incidence of cardiovascular events was low in all groups with the lowest incidence noted in group 3 (0.62%) followed by group 2 (0.92%) and group 1 (1.08%) (P-value = 0.619). Univariate and multivariate COX regression showed significant associations of age and hypertension with both LVEF decline and cardiovascular events. However, radiation therapy delivery and laterality were not significantly associated with either outcome. CONCLUSION: Our analysis of the HERA trial suggests that radiation therapy does not significantly increase the risk of cardiotoxicity in HER-2 positive breast cancer patients treated with trastuzumab. Continued monitoring of patients is needed to investigate late effects of contemporary treatments for breast cancer patients.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

In Reply to Belkacemi and Tsoutsou

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Post-Mastectomy Radiation Therapy in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer Patients: Analysis of the HERA Trial

Purpose: Postmastectomy radiation therapy (PMRT) improves recurrence rates and overall survival in breast cancer patients. However, it remains unclear whether these findings can be applied to human epidermal growth factor receptor 2 (HER-2) positive patients treated with trastuzumab. Methods and Materials: The Herceptin Adjuvant (HERA) trial is a phase III randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The present study is a retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models, and LRR curves were generated by the Kaplan-Meier method. Results: Our analysis included 940 patients (57.6%) who received PMRT and 693 patients (42.4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At a median follow-up of 11 years, no significant difference in LRR was noted after PMRT in node negative (N0) patients (P = .96). Patients with 1 to 3 positive lymph nodes had a LRR-free survival of 97% in the PMRT group compared with 90% in the no PMRT group (hazard ratio = 0.28, P = .004) and a nonsignificant improved overall survival after PMRT (hazard ratio = 0.63, P = .06). Conclusions: PMRT delivery in HER-2 positive breast cancer patients with 1 to 3 positive lymph nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historic studies, the present findings are in favor of PMRT for HER-2 positive breast cancer patients with 1 to 3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer patients benefit the most from PMRT.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection